Molecular Cancer Therapeutics最新文献

{"title":"Kinome Reprogramming of G2/M Kinases and Repression of MYCN Contribute to Superior Efficacy of Lorlatinib in ALK-Driven Neuroblastoma.","authors":"Smita Matkar, Michael P East, Timothy J Stuhlmiller, Gabriela M Witek, Alvin Farrel, Steven Pastor, Denis O Okumu, Anne Kennedy, Joshua R Kalna, Esther R Berko, Colleen E Casey, Kateryna Krytska, Khushbu Patel, Jo Lynne Rokita, Mark Gerelus, John M Maris, Gary L Johnson, Yael P Mossé","doi":"10.1158/1535-7163.MCT-24-0684","DOIUrl":"10.1158/1535-7163.MCT-24-0684","url":null,"abstract":"<p><p>Mutations in the tyrosine kinase domain of the anaplastic lymphoma kinase (ALK) oncogene in neuroblastoma occur most frequently at one of three hotspot amino acid residues, with the F1174* and F1245* variants conferring de novo resistance to first- and second-generation ALK inhibitors, including crizotinib and ceritinib. Lorlatinib, a third-generation ALK/ROS1 inhibitor, overcomes de novo resistance and induces complete and sustained tumor regressions in patient-derived xenograft models unresponsive to crizotinib. Lorlatinib has now completed phase 1 testing in children and adults with relapsed/refractory ALK-driven neuroblastoma and entered pivotal phase 3 testing within the Children's Oncology Group. To define mechanisms underlying the superior activity of lorlatinib, we utilized a chemical proteomics approach to quantitatively measure functional kinome dynamics in response to lorlatinib and crizotinib in clinically relevant ALK-driven neuroblastoma patient-derived xenograft models. Lorlatinib was a markedly more potent inhibitor of ALK and preferentially downregulated several kinases implicated in G2/M cell-cycle transition compared with crizotinib. Lorlatinib treatment also led to the repression of MYCN expression and its occupancy at promoters of the same G2/M kinases. These data provide mechanistic insight into the superior efficacy of lorlatinib over crizotinib for the treatment of ALK-driven neuroblastoma.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1389-1401"},"PeriodicalIF":5.5,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12322148/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"hmLIGHT Enhances Vaccine Antitumor Effects by Facilitating T-cell Infiltration and Activation in the 4T1 Breast Cancer Model.","authors":"Ling Dong, Shiqi Zhang, Qimuge Wuri, Xueli Qu, Ke Zhang, Zongyu Cai, Yaru Qiao, Mengfan Feng, Chu Wang, Hui Wu, Jiaxin Wu, Wei Kong, Xianghui Yu, Haihong Zhang","doi":"10.1158/1535-7163.MCT-24-0333","DOIUrl":"10.1158/1535-7163.MCT-24-0333","url":null,"abstract":"<p><p>Mounting evidence suggests that immunotherapies are promising strategies for fighting against cancers. However, the immunosuppressive tumor microenvironment (TME), insufficient lymphocytic infiltration, and poor immunogenicity hamper the broader implementation of immunotherapies. LIGHT, a member of the TNF superfamily, has been shown to recruit T cells into the TME, turning \"cold\" tumors into \"hot\" ones. Here, a human mutant LIGHT (hmLIGHT) protein has been obtained which successfully promoted the activation and proliferation of mouse CD8+ T cells via CD28-independent co-stimulatory activity. Moreover, direct intratumoral injection of VR-hmLIGHT remodeled the TME, enhanced CD8+ T-cell infiltration into tumors, and showed antitumor efficacy in 4T1 and CT26 tumor models. In addition, our previous studies of a DNA vaccine (OsFS) have shown promising antitumor activity. In this study, we evaluated a new combination of VR-hmLIGHT and OsFS to enhance efficacy in the 4T1 tumor model. The combined treatment has a remarkable antitumor effect, with a tumor inhibition rate of 70%, whereas OsFS and VR-hmLIGHT groups displayed 32% and 42% inhibition, respectively. These findings indicate the clinical potential of LIGHT as monotherapy or combination therapy.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1378-1388"},"PeriodicalIF":5.5,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143605387","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy of ATR Kinase Inhibitor Elimusertib Monotherapy or Combination in Tumors with DNA Damage Response Pathway and Other Genomic Alterations.","authors":"Kaushik Varadarajan, Christian X Cruz Pico, Kurt W Evans, Maria Gabriela Raso, Yasmeen Qamar Rizvi, Xiaofeng Zheng, Dhruv Chachad, Timothy P DiPeri, Bailiang Wang, Stephen M Scott, Ming Zhao, Argun Akcakanat, Antje M Wengner, Timothy A Yap, Funda Meric-Bernstam","doi":"10.1158/1535-7163.MCT-24-0884","DOIUrl":"10.1158/1535-7163.MCT-24-0884","url":null,"abstract":"<p><p>The ataxia telangiectasia and RAD3-related (ATR) kinase functions with ataxia telangiectasia-mutated (ATM) kinase as a modulator of DNA damage response (DDR). We assessed the antitumor effects of the ATR inhibitor elimusertib (BAY-1895344) in patient-derived xenograft (PDX) models with DDR alterations. Antitumor activity was assessed by change in tumor volume (TV) from baseline. Responses were categorized as follows: partial response (PR), ≥30% decrease in TV; ≥20% increase in TV, progressive disease; and non-PR/progressive disease, stable disease (SD). Event-free survival was defined as time for tumor doubling (EFS-2). Of 21 PDX models tested, 11 had significant prolongation of EFS-2 with elimusertib monotherapy. Four models had a PR and four had SD. PR/SD was observed in two of five models with ATM loss on IHC and in models with a variety of alterations in DDR genes, including BRCA1/2 and ATM. Elimusertib prolonged EFS-2 in three of five models with known PARP inhibitor resistance. Pharmacodynamic studies conducted in four PDX models showed an increase in DNA damage markers. PI3K/mTOR pathway signaling increased in two of four models. The combination of the PI3K inhibitor copanlisib with elimusertib enhanced EFS-2 compared with monotherapy in three of 11 models tested. The combination of elimusertib with the PARP inhibitor niraparib enhanced antitumor activity compared with single agents in PARP-resistant PDX models. Our study shows that ATR inhibition has antitumor activity, including in models with both intrinsic and acquired PARP inhibitor resistance. Further work is needed to better refine patient selection for ATR-based therapies.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1402-1414"},"PeriodicalIF":5.5,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12402799/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144024911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CRISPR Screens Identify POLB as a Synthetic Lethal Enhancer of PARP Inhibition Exclusively in BRCA-Mutated Tumors.","authors":"Katherine Lazarides, Justin L Engel, Michele Meseonznik, Tianshu Feng, Ashley H Choi, Yi Yu, Shangtao Liu, Samuel R Meier, Hongxiang Zhang, Binzhang Shen, Robert Tjin Tham Sjin, Douglas A Whittington, Brian J McMillan, Brian Doyon, Xuewen Pan, Erik Wilker, Alan Huang, Jannik N Andersen, William D Mallender, Madhavi Bandi","doi":"10.1158/1535-7163.MCT-24-0822","DOIUrl":"10.1158/1535-7163.MCT-24-0822","url":null,"abstract":"<p><p>PARP inhibitors (PARPi) are an approved class of anticancer therapeutics that inhibit the activities of PARP1/2 and produce synthetic lethality in BRCA1/2-mutated cancers because of the absence of a functional homologous recombination-dependent DNA repair pathway. Although PARPis have led to successful clinical outcomes, two thirds of patients develop acquired resistance, limiting long-term utility as maintenance therapy. Motivated by this clinical need, we utilized a CRISPR target discovery screening platform to identify DNA polymerase beta (POLB) as a gene that acts selectively and synergistically with PARPis in BRCA1/2-mutated cancers and found that POLB knockout (KO) along with PARPi treatment enhanced loss of viability in BRCA1/2-mutant and BRCA2-null cells but not in isogenic BRCA1/2 wild-type cells. Overexpression of either POLB wild-type or catalytically inactive mutants confirmed that perturbation of both the polymerase and lyase catalytic activities of POLB are required for synergistic PARP-BRCA synthetic lethality. Mechanistically, POLB KO was associated with an increase in single- and double-strand DNA breaks, cell-cycle arrest, and apoptosis when in combination with PARP inhibition. The translational nature of this interaction was further examined using murine xenograft models of BRCA1-mutant and BRCA2-null cell lines, wherein the combination of POLB KO and niraparib led to profound tumor regression and prevented tumor regrowth even after cessation of treatment. Together, these results suggest that POLB is a synergistic enhancer of the synthetic lethal interaction between PARP and BRCA and support POLB as a promising therapeutic target for improving antitumor responses to PARPis in homologous recombination-deficient cancers.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1466-1479"},"PeriodicalIF":5.5,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144024970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Discovery and Characterization of HBS-101, a Novel Inhibitor of Midkine, as a Therapeutic Agent for the Treatment of Triple-Negative Breast Cancer.","authors":"Megharani Mahajan, Alondra L Rodriguez Sanchez, Sridharan Jayamohan, Dileep K Vijayan, Jessica D Johnson, Huan Xie, Yang Wang, Dong Liang, John R Sanchez, Panneerdoss Subbarayalu, Manjeet K Rao, Ratna K Vadlamudi, Gangadhara R Sareddy, Hareesh B Nair, Suryavathi Viswanadhapalli","doi":"10.1158/1535-7163.MCT-25-0130","DOIUrl":"10.1158/1535-7163.MCT-25-0130","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a poor clinical outcome. There is a dire need for the development of new targeted therapies for TNBC. Midkine (MDK), a multifunctional cytokine/growth factor, functions as an oncoprotein, and its expression is elevated in various cancers. The absence of small-molecule inhibitors targeting MDK represents a significant knowledge gap for translation. In this study, we identified HBS-101 as a potent MDK inhibitor with high specificity. Our modeling studies revealed that the interaction of HBS-101 with MDK is primarily driven by hydrophobic forces, and this interaction disrupted MDK's binding to its endogenous receptors. Microscale thermophoresis, cellular thermal shift assay, and biotin pull-down studies confirmed the direct interaction of HBS-101 with MDK. Therapeutically, HBS-101 treatment significantly reduced cell viability (IC50 0.3-2.8 µmol/L), clonogenic survival, invasiveness, and increased apoptosis. The underlying mechanism of HBS-101 involves suppression of the Akt/mTOR, STAT3, and NF-κB pathways. Importantly, HBS-101 exhibits distinct pharmacologic advantages, including oral bioavailability, blood-brain barrier penetration, and in vivo stability. Histologically, doses of up to 10 mg/kg showed no observable organ toxicity and had no effect on the mice's body weight. Dose range studies identified 5 mg/kg as the minimal effective dose, achieving more than a 50% tumor reduction. HBS-101 treatment led to a significant reduction in the growth of xenograft tumors derived from patients with TNBC in vivo and markedly reduced TNBC brain metastatic tumor growth and prolonged mice survival. Collectively, our studies identified a first-in-class MDK inhibitor, HBS-101, that can be used to treat MDK-driven cancers.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1308-1319"},"PeriodicalIF":5.5,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12353485/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144033800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic Targeting of BET Proteins in Sarcoma.","authors":"Niknam Riyahi, Rada Malko, Harlan E Shannon, Kyle W Jackson, Ryli E Justice, Keiko Kreklau, M Reza Saadatzadeh, Karen E Pollok, Pankita H Pandya","doi":"10.1158/1535-7163.MCT-24-1027","DOIUrl":"10.1158/1535-7163.MCT-24-1027","url":null,"abstract":"<p><p>Bromodomain and extraterminal (BET) domain protein family are epigenetic readers that regulate gene transcription, cell-cycle progression, and DNA damage response (DDR), making them attractive therapeutic targets for sarcomas, which are epigenetically dysregulated and genomically unstable. Sarcomas are molecularly heterogeneous with a high propensity for metastasis, resulting in poor clinical outcomes. BET inhibitors (BETi) hold promise for the treatment of sarcomas, for they block interaction of BETs with acetylated lysines, modify gene expression, and create an imbalance in transcription and replication kinetics. BETis also disrupt transcriptional programs driven by oncogenic fusion proteins found in some sarcomas. Preclinical studies demonstrate efficacy of BETis in inducing apoptosis, disrupting DDR, and reducing tumor growth, either as monotherapy or in combination with chemotherapy or other targeted agents, such as PI3K, histone deacetylases, and CHK1 inhibitors. Favorable results have been observed in clinical trials, but more studies are required to fully assess safety and efficacy as well as identify biomarkers of response and resistance. Ongoing research is focused on optimizing BETi safety and selectivity and exploring combination therapies, such as BETis with DDR inhibitors. This review summarizes the preclinical studies on BET inhibition and discusses clinical trial activity, providing insights into the potential of BETis in sarcoma therapy.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1320-1330"},"PeriodicalIF":5.5,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12402787/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preclinical Evaluation of PTK7-Targeted Radionuclide Therapy.","authors":"Kim Lindland, Sara Westrøm, Srdan M Dragovic, Ruth Gong Li, Marion Masitsa Malenge, Betty Ho, Asta Juzeniene, Tina Bjørnlund Bønsdorff","doi":"10.1158/1535-7163.MCT-24-1060","DOIUrl":"10.1158/1535-7163.MCT-24-1060","url":null,"abstract":"<p><p>Protein tyrosine kinase 7 (PTK7), a receptor found in tumor-initiating cells, is expressed in various malignancies, including ovarian cancer. Whereas PTK7 has been explored as a target for antibody-drug conjugates, this study is the first to investigate its potential for targeted radionuclide therapy. We developed a murine monoclonal IgG1 antibody (mOI-1) using hybridoma technology and generated a chimeric version (chOI-1) with human IgG1 constant regions. A cell-based screening approach using a library of 6,100 cell surface proteins identified PTK7 as the target, confirmed by flow cytometry and surface plasmon resonance analyses. IHC showed strong PTK7 expression in ovarian cancer tissues, and in vitro studies demonstrated specific binding and internalization of OI-1 in the ovarian cancer cell line SKOV-3-luc. Biodistribution studies using 177Lu-DOTA-mOI-1 injected intravenously in xenograft mice with subcutaneous SKOV-3-luc revealed high tumor uptake and retention. Therapeutic efficacy was assessed by intraperitoneal treatment with 212Pb-TCMC-chOI-1 in an intraperitoneal xenograft model, showing significant tumor growth inhibition compared with nonradioactive controls. This study provides the first investigation of a PTK7-targeting antibody (OI-1) as an antibody-radionuclide conjugate (212Pb-labeled) in a preclinical model of intraperitoneal ovarian cancer. These results support further investigation of OI-1 as a candidate for targeted radionuclide therapy in PTK7-expressing cancers.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1415-1427"},"PeriodicalIF":5.5,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12402794/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144266742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of MCL-1 and MEK Overcomes MEK Inhibitor Resistance in Triple-Negative and Inflammatory Breast Cancers.","authors":"Mohd Mughees, Moises Tacam, Alex W Tan, Mary Kathryn Pitner, Lakesla R Iles, Xiaoding Hu, Emilly S Villodre, Bisrat G Debeb, Takahiro Kogawa, Bora Lim, Rachel M Layman, Wendy A Woodward, Naoto T Ueno, Debu Tripathy, Savitri Krishnamurthy, Yuan Qi, Lajos Pusztai, Jian Wang, Varsha Gandhi, Geoffrey Bartholomeusz, Chandra Bartholomeusz","doi":"10.1158/1535-7163.MCT-24-0593","DOIUrl":"10.1158/1535-7163.MCT-24-0593","url":null,"abstract":"<p><p>The MAPK pathway can drive resistance in highly aggressive breast cancers. Our previous work showed that the MEK inhibitor (MEKi) AZD6244 (selumetinib) prevented lung metastasis in a breast cancer xenograft model. In clinical studies, MEKis as single agents have had only modest activity against solid tumors due to the onset of resistance. Using synthetic lethality siRNA screening, we identified myeloid cell leukemia-1 (MCL-1) as a potential contributor to AZD6244 resistance. We hypothesized that MCL-1 promotes MEKi resistance in highly aggressive breast cancers and that MCL-1 inhibition overcomes AZD6244 resistance. We established two AZD6244-resistant cell lines: MDA-MB-231-R (triple-negative breast cancer) and SUM149-R (triple-negative inflammatory breast cancer). These resistant cells were characterized with respect to different parameters, and a combination of an MCL-1 inhibitor (MCL-1i) together with an MEKi was evaluated in vitro and in vivo to overcome the acquired resistance. Compared with their respective parental cells, MDA-MB-231-R and SUM149-R cells showed increased proliferation, colony formation, stemness, anchorage-independent growth, and MCL-1 expression levels. MCL-1 knockdown in resistant cells decreased cell proliferation and colony formation, increased apoptosis, and was associated with high expression of the proapoptotic proteins PUMA, NOXA, BAK, and BAX. MEKi resistance was overcome when resistant cells were treated with MCL-1i and MEKi combined. In an in vivo mouse model, inhibition of MCL-1 restored sensitivity to AZD6244. Our results suggest that MCL-1 is a driver of MEKi resistance and that combining an MCL-1i with an MEKi warrants further investigation in triple-negative and triple-negative inflammatory breast cancer.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1453-1465"},"PeriodicalIF":5.5,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12354021/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143979126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of mAb104, a mAb Targeting a Conformationally Exposed, Tumor-Specific Epitope of HER2.","authors":"Sagun Parakh, Nhi Huynh, Diana Dong Cao, Angela Rigopoulos, Benjamin Gloria, Ingrid J G Burvenich, Carmel Murone, Christian W Wichmann, Nancy Yanan Guo, Clare Senko, Adam Parslow, Laura Allan, Laura D Osellame, Peter W Janes, Fiona E Scott, Zhanqi Liu, Hui K Gan, Andrew M Scott","doi":"10.1158/1535-7163.MCT-24-0583","DOIUrl":"10.1158/1535-7163.MCT-24-0583","url":null,"abstract":"<p><p>We generated a novel HER2 mAb104, which binds to an epitope in domain II of HER2 that is conformationally exposed in tumors in response to HER2 amplification or activation but is not accessible to antibody binding in normal tissues. Consistent with other studies that evaluated antibodies targeting conformationally exposed epitopes, mAb104 lacked in vitro activity but showed potent antitumor activity in vivo. The antitumor effect in vivo was similar in magnitude to trastuzumab and pertuzumab, and combination with trastuzumab was superior to trastuzumab alone. IHC screening of normal and tumor tissues with mAb104 showed that mAb104 did not bind to normal tissues, confirming the tumor specificity of mAb104. In vivo biodistribution and imaging data demonstrated specific tumor targeting of mAb104 in HER2-expressing tumors. Confocal microscopy clearly demonstrated the internalization of mAb104 into the tumor cells, consistent with mAb104:HER2 trafficking. mAb104 is tumor-specific, exhibits potent antitumor activity in HER2-positive models, and internalizes into HER2-positive tumor cells. These results demonstrate the potential of mAb104 as a novel HER2-targeting therapy, both as a naked antibody for signaling abrogation therapy and for payload delivery as an antibody-drug conjugate or for β/α particle therapy.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1442-1452"},"PeriodicalIF":5.5,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12402785/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144018164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Anti-FRα Antibody-Drug Conjugate Luveltamab Tazevibulin Demonstrates Efficacy in Non-Small Cell Lung Cancer Preclinical Models and Induces Immunogenic Cell Death.","authors":"Robert Yuan, Andrew McGeehan, Sihong Zhou, Christine Cheng, Mark Armanini, Jennifer Smith, Millicent Embry, Rhoneil Pena, Danielle K Lewis, Genevive Hernandez, Krishna Bajjuri, Cuong Tran, Gang Yin, Cristina Abrahams, Xiaofan Li, Hans-Peter Gerber, Alice Yam, Helena Kiefel","doi":"10.1158/1535-7163.MCT-24-0649","DOIUrl":"10.1158/1535-7163.MCT-24-0649","url":null,"abstract":"<p><p>Luveltamab tazevibulin is a folate receptor α (FRα)-targeting antibody-drug conjugate currently being evaluated in phase I and II/III clinical trials in endometrial and ovarian cancers (NCT03748186 and NCT05870748), respectively. In this study, we report non-small cell lung cancer (NSCLC) as an additional cancer subtype enriched for FRα expression. In patient-derived xenograft models of NSCLC, FRα-expressing tumors demonstrated robust tumor growth inhibition following luveltamab tazevibulin treatment, demonstrating its potential use for NSCLC treatment. Luveltamab tazevibulin was additionally identified as a potent inducer of immunogenic cell death (ICD). In in vitro cell killing assays, luveltamab tazevibulin induced all three hallmarks of ICD-high mobility group box 1 release, ATP release, and surface exposure of calreticulin. Furthermore, in in vivo vaccination studies, injection of luveltamab tazevibulin-treated tumor cells established protective immunity against subsequent tumor challenge. Consistent with ICD induction, luveltamab tazevibulin treatment in tumor-bearing mice also altered tumor immune cell infiltrate and activation, demonstrating its ability to modulate the tumor immune microenvironment. Given the success of immune checkpoint therapy in NSCLC and luveltamab tazevibulin's ability to potentiate the immune response, we evaluated the combination therapy of luveltamab tazevibulin with immune checkpoint blockade in syngeneic mouse models and demonstrated that combination treatment results in enhanced efficacy compared with either monotherapy alone. This improved activity with combination therapy was associated with increased tumoral infiltration of CD8+ T cells. In conclusion, the work presented here provides rationale for evaluating luveltamab tazevibulin in NSCLC either as monotherapy or in combination with immune checkpoint blockade.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1428-1441"},"PeriodicalIF":5.5,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12402782/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143990432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}